Biomedical research is becoming increasingly dependent on construction and simulation of computational models. Arguably this will be even more the case with the development of personalized medicine. However, the technical aspects of modeling and simulation are overwhelming to many biomedical researchers. What is needed is a software application capable of providing the appropriate numerical algorithms, but shielded by a user interface that aides the biomedical researcher in conducting the required simulations. Modeling and simulation can be applied at the level of molecules, their networks, cells, tissues and whole organisms. Sometimes several of these levels have to be represented in order to properly predict and understand health and disease. Thus models are becoming larger, multiscale, and require various different mathematical frameworks for simulation. We propose to address this need with continuing development of the COPASI software, which is already widely used in the biomedical research community, addressing the current trends. This project will also provide support to the vibrant community of COPASI users/biomedical researchers. We will address this with the following Specific Aims: Aim 1. Add new numerical simulation and analysis methods to further support biomedical research. We will develop and add new hybrid simulation algorithms to address models that require some of its parts to be simulated in different frameworks. We will add a new task to analyze parameter identifiability, which is very useful for finding out if the model and data are matched, or improvements need to be made in both. Aim 2. Improve COPASI?s user interface and the interfaces with other software. We will improve the graphical user interface to allow it to efficiently manipulate very large models. We will create a new programming interface so that others can easily use COPASI?s functions from other programs. Aim 3. Software maintenance and standards compliance. We will continue to maintain the software, correcting errors and making improvements, guided by feedback collected from its users. We will continue to implement standards compliance to ensure the software is interoperable with other applications. Aim 4. Support the modeling community. We will continue outreach program activities aimed helping biomedical researchers make full use of the software?s capabilities. This includes continuing to offer tutorials, courses, and workshops? to create further training videos and to maintain a web-based discussion group.